Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2002-07-30
2003-10-14
Aulakh, Charanjit S. (Department: 2133)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C546S092000, C546S090000, C546S089000, C546S080000
Reexamination Certificate
active
06632418
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel radioligands and to methods for detecting specific activity of compounds. More particularly, the present specification discloses assays for detecting the binding of compounds to sites that regulate potassium channels.
BACKGROUND OF THE INVENTION
Potassium channels play important roles in regulating cell membrane excitability. In particular, ATP-sensitive potassium channels that are inhibited by intracellular ATP link cellular metabolism with membrane excitability in various cell types including cardiac, smooth muscle, neurons and secretory cells. In these cell types, K
ATP
channels modulate physiological processes including insulin secretion from pancreas, leptin release from hypothalamic neurons, synaptic transmission and excitability of cardiac, vascular and nonvascular smooth muscles. Openers of various K
ATP
channels can alter the cell's resting membrane potential and in turn cellular excitability to regulate these diverse processes. A number of diseases or conditions can be treated with therapeutic agents that open potassium channels. Such diseases or conditions include asthma, epilepsy, hypertension, sexual dysfunction, pain, migraine, urinary incontinence, stroke and neurodegeneration.
[
3
H]P1075 is a known radioligand for the ATP-sensitive potassium channel described by Brya et al., 1992. [
3
H]Bay X 9228 is another known radioligand for the ATP-senstive potassium channel. U.S. Pat. No. 5,328,830 discloses the utilization of tritiated (+)-N-(2-ethoxyphenyl)-N′-(1,2,2-trimethyl propyl)-2-nitroethene-1,1-diamine ([
3
H]CMPD), for assaying compounds whose activity is specific for ATP-sensitive potassium channels. However, the utility of these ligands are limited. These assays generally require intact cell or tissue preparations with large inherent variability due to poor specific activity and poor binding affinities Loffler-Walz, C., Quast, U. (1998) Br. J. Pharmacol., 123, 1395-1402.
Accordingly, a novel radioligand with improved potency and higher specific activity would be useful for characterization of K
ATP
channels in various tissues in addition to further investigation of the mechanism of action of novel potassium channel modulators with native and recombinant K
ATP
complex. The present invention relates to novel 1,4-dihydropyridine radioligands that have higher affinities and higher specific activity in interacting with the ATP-sensitive potassium channel. Specifically, the present invention discloses assays using novel 1,4-dihydropyridine radioligands for screening and identification of compounds that interact with ATP-sensitive potassium channels.
SUMMARY OF THE INVENTION
In one embodiment, the present invention discloses compounds of formula I:
or salts thereof wherein
n is an integer of 0-1;
m is an integer of 1-2;
provided that when n is 1, then m is 1;
A is selected from C(O) and S(O)
2
;
D is selected from O, S and CR
2
R
3
;
Z is selected from O and S;
R
1
is selected from alkyl, cyano, haloalkoxy, haloalkyl, halogen and nitro; and
R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are each independently selected from hydrogen and alkyl;
provided that when A is S(O)
2
; then D is CR
2
R
3
; and
further provided that when D is S; then n is 1 and A is C(O).
The compounds of the present invention are novel radioligands that bind to the ATP sensitive potassium channels. The present invention also relates to a binding assay that can be used to evaluate compounds that bind to a site that regulates the function of the K
+
channel complex. These compounds are useful for high throughput screening of compound libraries to identify novel ligands interacting with the ATP-sensitive potassium channels. Such radioligands could also be of utility in: (i) characterization of recombinant ATP-sensitive channel subunits; (ii) use as a tool to identify novel K
ATP
channel subunits (iii) study distribution of K
ATP
channels in situ in various tissues in physiological and disease states and (iv) in vivo imaging of ATP-sensitive potassium channels, including photoemission computed tomography.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention discloses compounds of formula I:
or salts thereof wherein
n is an integer of 0-1;
m is an integer of 1-2;
provided that when n is 1, then m is 1;
A is selected from C(O) and S(O)
2
;
D is selected from O, S and CR
2
R
3
;
Z is selected from O and S;
R
1
is selected from alkyl, cyano, haloalkoxy, haloalkyl, halogen and nitro; and
R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are each independently selected from hydrogen and alkyl;
provided that when A is S(O)
2
; then D is CR
2
R
3
; and
further provided that when D is S; then n is 1 and A is C(O).
In another embodiment, compounds of the present invention have formula (I) wherein R
1
is selected from alkyl, haloalkyl and halogen; R
4
, R
5
, R
6
and R
7
are each hydrogen; and m, n, A, D and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein n is 0; A is S(O)
2
; D is CR
2
R
3
; and m, Z, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein m is 1; n is 0; A is S(O)
2
; D is CR
2
R
3
; Z is O; R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are each hydrogen; and R
1
is as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein n is 0; A is C(O); D is CR
2
R
3
; and m, Z, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein n is 0; A is C(O); D is O; and m, Z, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein m is 1; n is 0; A is C(O); D is O; Z is O; R
4
, R
5
, R
6
and R
7
are each hydrogen; and R
1
is as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein n is 0; A is C(O); D is O; R
4
, R
5
and R
6
are each hydrogen; R
7
is alkyl; m, Z and R
1
are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein m is 1; n is 0; A is C(O); D is O; Z is O; R
4
, R
5
and R
6
are each hydrogen; R
7
is alkyl; and R
1
is as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein m is 1; n is 1; A is C(O); D is O; and Z, R
1
, R
4
, R
5
, R
6
and R
7
are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein m is 1; n is 1; A is C(O); D is O; R
4
, R
5
, R
6
and R
7
are each hydrogen; and Z and R
1
are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein m is 1; n is 1; A is C(O); D is O; Z is O; R
4
, R
5
, R
6
and R
7
are each hydrogen; and R
1
is as defined in formula (I).
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term “alkyl,” as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term “cyano,” as used herein, refers to a —CN group.
The term “halo” or “halogen,” as used herein, refers to —Cl, —Br, —I or —F.
The term “haloalkoxy,” as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term “haloalkyl,” as used herein, refers to at l
Altenbach Robert J.
Carroll William A.
Davis-Taber Rachel A.
Gopalakrishnan Murali
Molinari Eduardo Jose Vicente
Abbott Laboratories
Aulakh Charanjit S.
Ward Michaerl J.
LandOfFree
Radioligands and their use for identifying potassium channel... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Radioligands and their use for identifying potassium channel..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Radioligands and their use for identifying potassium channel... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3171639